How does the hippocampus transform experienced information (encode) and subsequently recall those memories (retrieve)? Our goal in this application is to reveal the mechanisms of encoding and retrieval in the hippocampal-entorhinal system (HES). During encoding and retrieval of spatial memory, the hippocampus communicates with the entorhinal cortex (EC) via coordination of theta (6-10Hz) and gamma (slow range ?25- 50Hz, fast range ?60-100Hz) oscillations. (Lisman and Jensen, 2013). For decades, theta and gamma oscillations have been proposed to have a role in memory processing, however, no studies have shown a direct causal role for theta and gamma oscillations in these processes. This research plan proposes to take advantage of multisite electrophysiology and closed-loop optogenetic stimulation to address two key hypotheses related to the role of theta and gamma oscillations in encoding and retrieval of spatial information. The first aim of the current proposal is to investigate the temporal dynamics of theta and slow/fast gamma coordination during encoding and retrieval of spatial memory. It is hypothesized that a dynamic alternation in theta-modulated slow and fast gamma coordination between CA3-CA1 and medial EC (MEC)-CA1 contributes to retrieval and encoding. However, this dynamic coordination of network activity during encoding and retrieval has never been experimentally observed. To test the above hypothesis, we will combine multisite electrophysiological recordings in CA3, CA1, and MEC in freely behaving mice performing a navigational task successfully applied in our lab (H-shaped maze) to distinguish encoding and retrieval (Siegle and Wilson, 2014). Theta and slow/fast gamma coherence will be analyzed in the CA3-CA1 and MEC-CA1 circuits during encoding and retrieval. In specific aim 2, we will determine the causal role of theta and gamma activity in hippocampal- entorhinal circuits during encoding and retrieval of spatial memory. First, it is hypothesized that entorhinal inputs at the trough of theta support encoding, whereas at the peak of theta intra-hippocampal (e.g., CA3-CA1) interactions support retrieval (Hasselmo et al., 2002). To test this hypothesis, we will use phase-specific closed- loop optogenetic manipulation to disrupt CA3-CA1 or MEC-CA1 circuits at the trough or peak of theta during encoding and retrieval of spatial memory. The second hypothesis suggests that coordinated slow gamma between CA3-CA1 circuits supports retrieval, whereas fast gamma coordination between MEC-CA1 circuits regulates encoding. To test this hypothesis, we will use activity-guide closed-loop optogenetic stimulation to disrupt specifically the coordination of slow or fast gamma activity in CA3-CA1 or MEC-CA1 circuits during encoding and retrieval. Spatial memory will be evaluated after closed-loop intervention. Success in these aims should provide the first causal link between theta- and slow/fast gamma-dependent modulation of entorhinal-hippocampal circuits and encoding/retrieval of spatial information.